This invention is in the fields of chemistry and pharmacology, and relates to drugs that can inhibit adenosine deaminase. Such drugs can be used to reduce the metabolic degradation of chemotherapeutic and anti-viral drugs.
The compound erythro-hydroxynonyladenine (EHNA, which is usually pronounced as "eenah") is known to inhibit the activity of an enzyme called adenosine deaminase (ADA, also known as adenosine aminohydrolase). ADA, which is designated E.C.3.5.4.4 under the international classification system, converts adenosine into inosine by removing an amine group which is attached to the #6 carbon in the two-ring adenyl structure of adenosine.
ADA can also degrade a number of other molecules, including several nucleoside analogs that are used in cancer chemotherapy or for anti-viral therapy. Therefore, ADA inhibitors can be used as adjuncts (i.e., as secondary agents to increase the effectiveness of a primary drug) to prolong the metabolic half-lives of therapeutic drugs during cancer or anti-viral chemotherapy. ADA inhibitors can also be used to artificially create ADA deficiencies, which are of interest to researchers.
EHNA, a relatively mild ADA inhibitor, is a stereoisomer with the following chemical structure, which shows the numbering of the carbon atoms in the side chain (i.e., in the erythro-hydroxynonyl structure that is attached to the adenyl group): ##STR1##
The "erythro-" prefix indicates a certain stereoisomeric arrangement of the atoms attached to the #2 and #3 carbon atoms, which are both chiral atoms. Other isomers having a different stereoisomeric arrangement are often referred to as "threo-" compounds. A racemic mixture (i.e., a mixture containing both D (+) and L isomers) containing EHNA was identified as an ADA inhibitor in Schaeffer and Schwender 1974. Subsequent reports, including Bastian et al 1981 and Baker and Hawkins 1982, identified the (+)-2S,3R isomer as the most potent ADA inhibitor from among the various hydroxynonyladenine isomers.
Various analogs and derivatives of EHNA have been described in reports such as Harriman et al 1992. Those other analogs are not related to the EHNA analogs described herein.
EHNA apparently is metabolized and cleared from the mammalian bloodstream fairly rapidly (McConnell et al 1980; Lambe and Nelson 1982). In addition, ADA inhibition by EHNA is not as strong as certain other known compounds, including deoxycoformycin (dCF, also known as Pentostatin). The Ki value of dCF (i.e., the concentration of dCF required to inactivate a standardized quantity of ADA) is very low, about 2.5.times.10.sup.-12 which indicates that dCF binds to ADA very tightly; dCF is sometimes called a "suicide inhibitor," which indicates that the binding between dCF and ADA is effectively irreversible and neither molecule can be regenerated. Because of its potency as an ADA inhibitor, dCF has been tested by several research teams to determine whether it can be used therapeutically. Although dCF reportedly provided some beneficial activity in cardiovascular models (e.g., Dorheim et al 1991) and in neuroprotective models (e.g., Phillis and O'Regan 1989), it was found to cause serious and unpredictable toxic side effects in some animals. Therefore, attention has returned to EHNA as a milder or "softer" ADA inhibitor with fewer side effects. The Ki value of EHNA is about 4.times.10.sup.-9, which indicates that EHNA binds to ADA about a thousand times less tightly than dCF.
One object of this invention is to disclose a class of hydroxylated derivatives of EHNA which can inhibit ADA activity at therapeutically effective levels without irreversibly inactivating (poisoning) the ADA enzyme.
Another object of this invention is to disclose synthetic reagents and methods that can be used to create analogs of EHNA which contain hydroxyl, halide, acid, ester, ether, amine, azide, or other moieties at various controllable locations in the side chain.
Another object of this invention is to disclose a new set of EHNA analogs which can be used to slow down the degradation of certain types of useful therapeutic drugs by ADA.